Epithelial barrier disruption allows nondisease-causing bacteria to initiate and sustain IBD in the IL-10 gene-deficient mouse

Authors

  • Beate C. Sydora PhD,

    1. Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
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  • Sarah M. MacFarlane,

    1. Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
    2. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
    3. Vernon General Hospital, Vernon, British Columbia, Canada
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  • John W. Walker PhD,

    1. Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
    2. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
    3. Vernon General Hospital, Vernon, British Columbia, Canada
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  • Andrea L. Dmytrash MSc,

    1. Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
    2. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
    3. Vernon General Hospital, Vernon, British Columbia, Canada
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  • Thomas A. Churchill PhD,

    1. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
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  • Jason Doyle MD,,

    1. Vernon General Hospital, Vernon, British Columbia, Canada
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  • Richard N. Fedorak MD

    Corresponding author
    1. Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
    • Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, Zeidler Ledcor Centre, University of Alberta, Edmonton, Alberta T6G 2X8, Canada
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  • We thank the University of Alberta Health Sciences Laboratory Animal Services.

Abstract

Background: In the IL-10 gene-deficient mouse model, development of intestinal inflammation is associated with a defect in epithelial barrier integrity that is thought to allow sufficient passage of bacteria or bacterial antigens to initiate a mucosal immune response. Microbial monoassociation experiments into axenic animals have shown that some, but not all, endogenous bacteria will initiate an intestinal inflammatory response. For instance, Bacteroides vulgatus does not initiate intestinal inflammation in axenic IL-10 gene-deficient mice. We investigated whether B. vulgatus requires concomitant disruption of the intestinal epithelial barrier integrity in order to initiate an inflammatory response.

Methods: We first identified a dose of the indomethacin that would cause a primary disruption of the epithelial barrier without causing intestinal inflammation. IL-10 axenic mice were then administered this dose of indomethacin in their drinking water for 7 days and concomitantly monoassociated, by oral gavage, with B. vulgatus.

Results: Indomethacin treatment (2 μg/g/d) for 7 days resulted in disruption of epithelial barrier integrity, but it caused neither a systemic inflammatory response nor a mucosal inflammatory response in the colon or cecum. Monoassociation with B. vulgatus alone did not lead to a mucosal inflammatory response, despite a measurable systemic response. In contrast, administration of indomethacin plus B. vulgatus-monoassociation resulted in a marked intestinal inflammatory response in colon and cecum.

Conclusions: Our data show that, in a genetically predisposed animal model, the nondisease-causing endogenous bacteria, B. vulgatus, is able to cause an intestinal inflammatory response provided that disruption of the intestinal epithelial barrier has occurred.

(Inflamm Bowel Dis 2007)

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